Appel (Ann. Neurol. 10:499, 1981) has recently suggested that the cholinergic dysfunction observed in the brains of patients with dementia of the Alzheimer's type (DAT) results from lack of a neurotrophic hormone released from target cells of cholinergic afferents which is necessary for the continued survival of the afferent neurons. If this hypothesis were true, it is possible that the neuronal loss and degeneration of central cholinergic systems in DAT could be reduced by treatment with CNFs. It has been demonstrated that CNFs released from cholinergically innervated peripheral organs or CNS regions promote the survival and growth of peripheral cholinergic neurons in vitro (e.g. Helfan et. al. Devel. Bio. 50:541, 1976) and the regenerative growth of cholinergic neurons in brain into peripheral tissue implants (Schonfeld et. al. Brain Res. 229:541, 1981). The aim of the current proposal is to determine the efficacy of CNFs released from heart or eye tissue to facilitate the restoration of appropriate innervation of brain areas in situ by mature CNS cholinergic fibers. For this, the septohippocampal pathway of rats will be lesioned and intraseptal cannulae will be inserted for repeated administration of either CNF or control vehicle. Possible CNS neurotrophic effects of CNFs which will be monitored include: 1. potentiation of neuritic outgrowth by measurement of hippocampal choline acetyltransferase; 2. regional specificity by analysis of intrahippocampal staining for acetylcholinesterase; 3. enhancement of muscarinic receptor binding by measurement of hippocampal concentration of 3H-quinuclidinyl benzilate; and 4. directional guidance by mapping the distribution of the regenerating fibers autoradiographically. The results of this project should reveal whether CNFs derived from peripheral organs can promote the restoration of appropriate innervation of cholinergically denervated brain regions by adult cholinergic axons. These studies will provide information concerning the therapeutic potential of CNFs independent of experimental demonstration of the possible lack of CNFs in the etiology of Alzheimer's disease.